Summary/Abstract In humans, loss of the hair cells in the inner ear leads to hearing and balance impairment, since these cells do not regenerate. By contrast, in non-mammalian vertebrates, like birds and fish, damaged auditory hair cells are regenerated very efficiently from the surrounding supporting cells. The ability of support cells to give rise to hair cells through transdifferentiation was first demonstrated by Corwin in the amphibian lateral line, by direct observation using time-lapse imaging, but more indirect methods also found a similar process to occur in bird basilar papilla. These results together suggest that the problem of hair cell regeneration in the inner ear of the mammal can be summarized in two fundamental questions: (1) What causes the loss in proliferation of support cells following damage and (2) what limits the transdifferentiation of the support cells to new hair cells? In this grant application we aim to study what are the factors that limit regeneration in the vestibular system of the mammal. We will use various transgenic strains to activate pathways that may lead to stimulation of hair cell regeneration. We will specifically direct our studies towards the crista (the sensory regions at the base of the three semicircular canals) that detect head rotation in the three ordinal planes. As the population ages balance disorders become more prevalent and this organ is particularly important for maintaining gaze. The cristae have been understudied at the molecular level to date and we have recently developed a culture method and are using advanced molecular techniques to elucidate changes in the competence of crista support cells to generate hair cells.